Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community (Klausner et al, Science 5628:2036-2039 (2003); Esparza et al, Science Strategic Plan, DOI: 10.1371/journal.pmed.0020025, Policy Forum Vol. 2, February 2005)). While anti-retroviral treatment (ART) has dramatically prolonged the lives of HIV-1 infected patients, anti-retroviral therapy is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated.
A recent study of the immune correlates of the RV144 vaccine trial (Rerks-Ngarm et al, N. Eng. J. Med. 361: 2209-20 (2009)) demonstrated that plasma V1V2 antibodies against a scaffolded V1V2-gp70 construct (Pinter et al, Vaccine 16:1803-11 (1998)), was associated with decrease risk of infection in vaccines (Haynes et al, Immune Correlates Analysis of the ALVAC-AIDSVAX HIV-1 Vaccine Efficacy Trial. N. Eng. J. Med., Submitted (2011)). This vaccine trial, however, induced only modest efficacy with an estimated 31.2% vaccine efficacy (Rerks-Ngarm et al, N. Eng. J. Med. 361: 2209-20 (2009)). To design immunogens with the capacity to induce better immune responses to an immunogen, it is critical to design immunogens capable of binding to the unmutated ancestors and the intermediate clonal lineage antibodies of the mature mutated types of antibodies to be induced (Dal Porto et al, J Exp Med 195:1215-1221 (2002); Shih et al, Nat Immunol 3:570-575 (2002); Schwickert et al, J Exp Med 208:1243-1252 (2011); Bonsignori et al, J Virol 85:9998-10009 (2011); Ma et al, PLoS Pathog 7(9): e1002200 (2011); Liao et al, J Exp Med 208:2237-49 (2011); and Alam et al, J Virol 85: 11725-31 (2011)).
In 2012 an immune correlates study of the RV144 trial revealed that antibodies against the Env gp120 V1/V2 region presented on a gp70-V1/V2 fusion protein were associated with lower risk of infection (Haynes et al, TNew Engl. J. Med. 366:1275-1286 (2012)). Epitope mapping of plasma V1/V2 antibody responses showed that within V2, vaccine-induced antibodies targeted a region of HIV-1 Env, amino acid (aa) residues at positions 163-178 (Karasavvas et al; AIDS Research and Human Retroviruses, doi:10.1089/aid.2012.0103 (2012), Zolla-Pazner et al, AIDS Vaccine. Bangkok, Thailand Abstract No.: OA09.03, 77 (2011)). There is considerable sequence variability in V1/V2, ˜75% of the residues are conserved or demonstrated to be only conservative changes (Zolla-Pazner & Cardozo, Nat Rev Immunol 10, 527-535 (2010)). While the demonstration that of V1/V2 antibody responses directly correlated with decreased infection risk was suggestive of their protective role in the trial, this association was not sufficient for proving causation of protection (Plotkin & Gilbert, Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 54:1615-1617 doi:10.1093/cid/cis238 (2012)). Indeed further studies are needed to evaluate the ability of such responses to mediate immune pressure on HIV-1. Viral genetic (sieve) analyses, isolation of V1/V2 antibodies and understanding their effector function in vitro and in vivo, and validation of correlates of infection risk in future vaccine trials are some potential studies.
A genetic or sieve analysis of sequences of viruses that caused breakthrough infections in a vaccine trial can demonstrate vaccine effects (Rolland et al, Nature Medicine 17:366-371 (2011)). By comparing sequences of breakthrough infections that occur in vaccines versus placebo recipients, sites of vaccine-induced immune pressure can be identified (Rolland et al, Nature Medicine 17:366-371 (2011)). A recent genetic analysis of breakthrough HIV-1 infections in the RV144 trial demonstrated 48% (CI: 18 to 68%, p=0.0036) vaccine efficacy against viruses matching the CRF_01AE vaccine immunogens with a lysine (K) at position 169 (Rolland et al, Nature 490:417-420 (2012)). Thus, it is critical to determine the binding site and effector functions of RV144-induced V1/V2 antibodies. Effector functions considered for antibody mediated-protection from HIV-1 transmission include the ability of V1/V2 antibodies to neutralize those virus strains involved in HIV-1 transmission (i.e. transmitted/founder viruses) (Keele et al, Proc Natl Acad Sci USA. 105:7552-7557 (2008)), and/or to mediate other antibody effector functions such as antibody-dependent cellular cytotoxicity (ADCC) (Haynes et al, New Engl. J. Med. 366:1275-1286 (2012)).
The present invention results, at least in part, from studies associated with the isolation of V2 neutralizing antibodies from RV144 vaccines blood mononuclear memory B cells (mAbs CH58 and CH59) as well as the isolation of a clonal lineage of HIV-1 broad neutralizing V1V2 conformational gp120 envelope monoclonal antibodies (CH01-CH04) (Bonsignori et al, J Virol 85:9998-10009 (2011)). The present invention provides, at least in part, new vaccine immunogens that induce high titers of vaccine responses to V1V2 of HIV-1 envelope gp120. The invention also results, at least in part, from studies involving the probing of the specificities and effector functions of four V2 monoclonal antibodies (mAbs) isolated from RV144 ALVAC/AIDSVAX vaccine recipients, and the determination of crystal structures of two of these mAbs with V2 peptides containing position 169.